Abstract
Objective: High lipophilicity and extensive hepatic metabolism limit oral application of orlistat in obesity treatment. Orlistat-loaded chitosan nanoparticles (CONPs) were optimized by 3-factor 3-level Box–Behnken design (BBD) and surfaced engineered to address limitations.
 Methods: CONPs were prepared by ionic gelation method. Amounts of chitosan (X1), sodium tripoly phosphate (X2), and orlistat (X3) were selected as independent factors, whereas % entrapment efficiency (Y1) and % drug release (Y2) were employed as responses in BBD. Three-dimensional response surface plots were run to understand the main interaction and quadratic effects of independent variables. Further optimized formulation was surface engineered by Eudragit L-100 (ECONPs) and characterized by FTIR, DSC, XRD, particle size, zeta potential, and SEM. Entrapment efficiency, release kinetics, stability, and in vitro cell line studies were carried out.
 Results: ECONPs were produced with an average size of 534.6 nm, zeta potential of +5.7 mV, EE of 78.62%, and DR of 80.86%. Eudragit coated CONPs anchored the release of orlistat at pH 6.8 desirable for duodenal targeting. Orlistat was released with low, burst, and sustained release manner over 24 h period followed first-order kinetics with Higuchi model with drug content of 84.87% and 78.44% of release. ECONPs possessed lipase inhibition with IC50 value of 8.0 μg/ml and viability against selected cell lines with CTC50 values (26.32–32.21 μg/ml).
 Conclusion: BBD was a promising tool in elucidating the insights of formulation variables of CONPs. ECONPs fulfilled the rationale of orlistat release, lipase inhibition, and viability against selected cell lines.
Highlights
The World Health Organization (WHO) pronounces that the obesity is as a chronic metabolic disease which affects 13% of world’s population and its prevalence was tripled between 1975 and 2016 [1]
Obtained values clearly indicated the EE and DR of chitosan nanoparticles (CONPs) were influenced by selected variables
Attribution was fortified with reduced intensity of characteristic peaks of orlistat which was due to dilution and partial solid state interaction of orlistat as evident a b Fig. 10: (a) Fourier Transform Infrared (FTIR) spectra of Eudragit L coated CONPs (ECONPs) from stability study, (b) drug release profiles of ECONPs with Fig. 7
Summary
The World Health Organization (WHO) pronounces that the obesity is as a chronic metabolic disease which affects 13% of world’s population and its prevalence was tripled between 1975 and 2016 [1]. Fibrates, lipase inhibitors, bile acid sequesterants, and nicotinic acid derivatives are currently employed for the treatment of hyperlipidemia and obesity [4], but their therapeutic effectiveness is limited due to unavailability of targeted formulations. Orlistat (tetrahydrolipstatin) is a lipase inhibitor and has poor water solubility, low melting point, low chemical stability, extensive first pass metabolism, waxy nature, and poor bioavailability (
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